Genome-wide association study of blood pressure and hypertension

Daniel Levy; Georg B. Ehret; Kenneth Rice; Germaine C. Verwoert; Lenore J. Launer; Abbas Dehghan; Nicole L. Glazer; Alanna C. Morrison; Andrew D. Johnson; Thor Aspelund; Yurii Aulchenko; Thomas Lumley; Anna Köttgen; Ramachandran S. Vasan; Fernando Rivadeneira; Gudny Eiriksdottir; Xiuqing Guo; Dan E. Arking; Gary F. Mitchell; Francesco U.S. Mattace-Raso; Albert V. Smith; Kent Taylor; Robert B. Scharpf; Shih Jen Hwang; Eric J.G. Sijbrands; Joshua Bis; Tamara B. Harris; Santhi K. Ganesh; Christopher J. O'Donnell; Albert Hofman; Jerome I. Rotter; Josef Coresh; Emelia J. Benjamin; André G. Uitterlinden; Gerardo Heiss; Caroline S. Fox; Jacqueline C.M. Witteman; Eric Boerwinkle; Thomas J. Wang; Vilmundur Gudnason; Martin G. Larson; Aravinda Chakravarti; Bruce M. Psaty; Cornelia M. Van Duijn

doi:10.1038/ng.384

Genome-wide association study of blood pressure and hypertension

Daniel Levy, Georg B. Ehret, Kenneth Rice, Germaine C. Verwoert, Lenore J. Launer, Abbas Dehghan, Nicole L. Glazer, Alanna C. Morrison, Andrew D. Johnson, Thor Aspelund, Yurii Aulchenko, Thomas Lumley, Anna Köttgen, Ramachandran S. Vasan, Fernando Rivadeneira, Gudny Eiriksdottir, Xiuqing Guo, Dan E. Arking, Gary F. Mitchell, Francesco U.S. Mattace-RasoAlbert V. Smith, Kent Taylor, Robert B. Scharpf, Shih Jen Hwang, Eric J.G. Sijbrands, Joshua Bis, Tamara B. Harris, Santhi K. Ganesh, Christopher J. O'Donnell, Albert Hofman, Jerome I. Rotter, Josef Coresh, Emelia J. Benjamin, André G. Uitterlinden, Gerardo Heiss, Caroline S. Fox, Jacqueline C.M. Witteman, Eric Boerwinkle, Thomas J. Wang, Vilmundur Gudnason, Martin G. Larson, Aravinda Chakravarti, Bruce M. Psaty, Cornelia M. Van Duijn

Research output: Contribution to journal › Article › peer-review

1142 Scopus citations

Abstract

Blood pressure is a major cardiovascular disease risk factor. To date, few variants associated with interindividual blood pressure variation have been identified and replicated. Here we report results of a genome-wide association study of systolic (SBP) and diastolic (DBP) blood pressure and hypertension in the CHARGE Consortium (n = 29,136), identifying 13 SNPs for SBP, 20 for DBP and 10 for hypertension at P 4 × 10 7. The top ten loci for SBP and DBP were incorporated into a risk score; mean BP and prevalence of hypertension increased in relation to the number of risk alleles carried. When ten CHARGE SNPs for each trait were included in a joint meta-analysis with the Global BPgen Consortium (n = 34,433), four CHARGE loci attained genome-wide significance (P 5 × 10 8) for SBP (ATP2B1, CYP17A1, PLEKHA7, SH2B3), six for DBP (ATP2B1, CACNB2, CSK-ULK3, SH2B3, TBX3-TBX5, ULK4) and one for hypertension (ATP2B1). Identifying genes associated with blood pressure advances our understanding of blood pressure regulation and highlights potential drug targets for the prevention or treatment of hypertension.

Original language	English (US)
Pages (from-to)	677-687
Number of pages	11
Journal	Nature genetics
Volume	41
Issue number	6
DOIs	https://doi.org/10.1038/ng.384
State	Published - Jun 2009
Externally published	Yes

ASJC Scopus subject areas

Genetics

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10.1038/ng.384

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Levy, D., Ehret, G. B., Rice, K., Verwoert, G. C., Launer, L. J., Dehghan, A., Glazer, N. L., Morrison, A. C., Johnson, A. D., Aspelund, T., Aulchenko, Y., Lumley, T., Köttgen, A., Vasan, R. S., Rivadeneira, F., Eiriksdottir, G., Guo, X., Arking, D. E., Mitchell, G. F., ... Van Duijn, C. M. (2009). Genome-wide association study of blood pressure and hypertension. Nature genetics, 41(6), 677-687. https://doi.org/10.1038/ng.384

Levy, D, Ehret, GB, Rice, K, Verwoert, GC, Launer, LJ, Dehghan, A, Glazer, NL, Morrison, AC, Johnson, AD, Aspelund, T, Aulchenko, Y, Lumley, T, Köttgen, A, Vasan, RS, Rivadeneira, F, Eiriksdottir, G, Guo, X, Arking, DE, Mitchell, GF, Mattace-Raso, FUS, Smith, AV, Taylor, K, Scharpf, RB, Hwang, SJ, Sijbrands, EJG, Bis, J, Harris, TB, Ganesh, SK, O'Donnell, CJ, Hofman, A, Rotter, JI, Coresh, J, Benjamin, EJ, Uitterlinden, AG, Heiss, G, Fox, CS, Witteman, JCM, Boerwinkle, E, Wang, TJ, Gudnason, V, Larson, MG, Chakravarti, A, Psaty, BM & Van Duijn, CM 2009, 'Genome-wide association study of blood pressure and hypertension', Nature genetics, vol. 41, no. 6, pp. 677-687. https://doi.org/10.1038/ng.384

@article{2bb378b0cdc74b4db299c6a084347703,

title = "Genome-wide association study of blood pressure and hypertension",

abstract = "Blood pressure is a major cardiovascular disease risk factor. To date, few variants associated with interindividual blood pressure variation have been identified and replicated. Here we report results of a genome-wide association study of systolic (SBP) and diastolic (DBP) blood pressure and hypertension in the CHARGE Consortium (n = 29,136), identifying 13 SNPs for SBP, 20 for DBP and 10 for hypertension at P 4 × 10 7. The top ten loci for SBP and DBP were incorporated into a risk score; mean BP and prevalence of hypertension increased in relation to the number of risk alleles carried. When ten CHARGE SNPs for each trait were included in a joint meta-analysis with the Global BPgen Consortium (n = 34,433), four CHARGE loci attained genome-wide significance (P 5 × 10 8) for SBP (ATP2B1, CYP17A1, PLEKHA7, SH2B3), six for DBP (ATP2B1, CACNB2, CSK-ULK3, SH2B3, TBX3-TBX5, ULK4) and one for hypertension (ATP2B1). Identifying genes associated with blood pressure advances our understanding of blood pressure regulation and highlights potential drug targets for the prevention or treatment of hypertension.",

author = "Daniel Levy and Ehret, {Georg B.} and Kenneth Rice and Verwoert, {Germaine C.} and Launer, {Lenore J.} and Abbas Dehghan and Glazer, {Nicole L.} and Morrison, {Alanna C.} and Johnson, {Andrew D.} and Thor Aspelund and Yurii Aulchenko and Thomas Lumley and Anna K{\"o}ttgen and Vasan, {Ramachandran S.} and Fernando Rivadeneira and Gudny Eiriksdottir and Xiuqing Guo and Arking, {Dan E.} and Mitchell, {Gary F.} and Mattace-Raso, {Francesco U.S.} and Smith, {Albert V.} and Kent Taylor and Scharpf, {Robert B.} and Hwang, {Shih Jen} and Sijbrands, {Eric J.G.} and Joshua Bis and Harris, {Tamara B.} and Ganesh, {Santhi K.} and O'Donnell, {Christopher J.} and Albert Hofman and Rotter, {Jerome I.} and Josef Coresh and Benjamin, {Emelia J.} and Uitterlinden, {Andr{\'e} G.} and Gerardo Heiss and Fox, {Caroline S.} and Witteman, {Jacqueline C.M.} and Eric Boerwinkle and Wang, {Thomas J.} and Vilmundur Gudnason and Larson, {Martin G.} and Aravinda Chakravarti and Psaty, {Bruce M.} and {Van Duijn}, {Cornelia M.}",

note = "Funding Information: The authors acknowledge the essential role of the Cohorts for Heart and Aging Research in Genome Epidemiology (CHARGE) Consortium in development and support of this manuscript. CHARGE members include The Netherland{\textquoteright}s Rotterdam Study (RS), Framingham Heart Study (FHS), Cardiovascular Health Study (CHS), the NHLBI{\textquoteright}s Atherosclerosis Risk in Communities (ARIC) Study, and the NIA{\textquoteright}s Iceland Age, Gene/Environment Susceptibility (AGES) Study. AGES: The Age, Gene/Environment Susceptibility Reykjavik Study is funded by NIH contract N01-AG-12100, the NIA Intramural Research Program, Hjartavernd (the Icelandic Heart Association) and the Althingi (the Icelandic Parliament). ARIC: The Atherosclerosis Risk in Communities Study is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute contracts N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021 and N01-HC-55022, and grants R01HL087641, R01HL59367, R37HL051021, R01HL086694 and U10HL054512; National Human Genome Research Institute contract U01HG004402; and National Institutes of Health contract HHSN268200625226C. Infrastructure was partly supported by Grant Number UL1RR025005, a component of the National Institutes of Health and NIH Roadmap for Medical Research. A.K. is supported by a German Research Foundation Fellowship. CHS: The Cardiovascular Health Study was supported by contract numbers N01-HC-85079 through N01-HC-85086, N01-HC-35129, N01 HC-15103, N01 HC-55222, N01-HC-75150, N01-HC-45133, grant numbers U01 HL080295 and R01 HL087652 from the National Heart, Lung, and Blood Institute. A full list of principal CHS investigators and institutions can be found at http://www. chs-nhlbi.org/pi.htm. FHS: The National Heart, Lung, and Blood Institute{\textquoteright}s Framingham Heart Study is a joint project of the National Institutes of Health and Boston University School of Medicine and was supported by the National Heart, Lung, and Blood Institute{\textquoteright}s Framingham Heart Study (contract No. N01-HC-25195) and its contract with Affymetrix, Inc. for genotyping services (contract No. N02-HL-6-4278). Analyses reflect the efforts and resource development from the Framingham Heart Study investigators participating in the SNP Health Association Resource (SHARe) project. A portion of this research was conducted using the Linux Cluster for Genetic Analysis (LinGA-II) funded by the Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center. RS: The Rotterdam Study is supported by the Erasmus Medical Center and Erasmus University Rotterdam; the Netherlands Organization for Scientific Research; the Netherlands Organization for Health Research and Development (ZonMw); the Research Institute for Diseases in the Elderly (RIDE); The Netherlands Heart Foundation; the Ministry of Education, Culture and Science; the Ministry of Health Welfare and Sports; the European Commission (DG XII); the Municipality of Rotterdam and the ErasmusMC translational research fund (2004-44). Support for genotyping was provided by the Netherlands Organization for Scientific Research (NWO Groot, 175.010.2005.011, 911.03.012) and Research Institute for Diseases in the Elderly (014.93.015; RIDE2). This study was supported by the Netherlands Genomics Initiative (NGI)/Netherlands Organisation for Scientific Research (NWO) project nr. 050-060-810. We thank P. Arp, M. Jhamai, M. Moorhouse, M. Verkerk and S. Bervoets for their help in creating the database and M. Struchalin for his contributions to the imputations of the data. The authors are grateful to the study participants, the staff from the Rotterdam Study and the participating general practioners and pharmacists.",

year = "2009",

month = jun,

doi = "10.1038/ng.384",

language = "English (US)",

volume = "41",

pages = "677--687",

journal = "Nature genetics",

issn = "1061-4036",

publisher = "Nature Publishing Group",

number = "6",

}

TY - JOUR

T1 - Genome-wide association study of blood pressure and hypertension

AU - Levy, Daniel

AU - Ehret, Georg B.

AU - Rice, Kenneth

AU - Verwoert, Germaine C.

AU - Launer, Lenore J.

AU - Dehghan, Abbas

AU - Glazer, Nicole L.

AU - Morrison, Alanna C.

AU - Johnson, Andrew D.

AU - Aspelund, Thor

AU - Aulchenko, Yurii

AU - Lumley, Thomas

AU - Köttgen, Anna

AU - Vasan, Ramachandran S.

AU - Rivadeneira, Fernando

AU - Eiriksdottir, Gudny

AU - Guo, Xiuqing

AU - Arking, Dan E.

AU - Mitchell, Gary F.

AU - Mattace-Raso, Francesco U.S.

AU - Smith, Albert V.

AU - Taylor, Kent

AU - Scharpf, Robert B.

AU - Hwang, Shih Jen

AU - Sijbrands, Eric J.G.

AU - Bis, Joshua

AU - Harris, Tamara B.

AU - Ganesh, Santhi K.

AU - O'Donnell, Christopher J.

AU - Hofman, Albert

AU - Rotter, Jerome I.

AU - Coresh, Josef

AU - Benjamin, Emelia J.

AU - Uitterlinden, André G.

AU - Heiss, Gerardo

AU - Fox, Caroline S.

AU - Witteman, Jacqueline C.M.

AU - Boerwinkle, Eric

AU - Wang, Thomas J.

AU - Gudnason, Vilmundur

AU - Larson, Martin G.

AU - Chakravarti, Aravinda

AU - Psaty, Bruce M.

AU - Van Duijn, Cornelia M.

N1 - Funding Information: The authors acknowledge the essential role of the Cohorts for Heart and Aging Research in Genome Epidemiology (CHARGE) Consortium in development and support of this manuscript. CHARGE members include The Netherland’s Rotterdam Study (RS), Framingham Heart Study (FHS), Cardiovascular Health Study (CHS), the NHLBI’s Atherosclerosis Risk in Communities (ARIC) Study, and the NIA’s Iceland Age, Gene/Environment Susceptibility (AGES) Study. AGES: The Age, Gene/Environment Susceptibility Reykjavik Study is funded by NIH contract N01-AG-12100, the NIA Intramural Research Program, Hjartavernd (the Icelandic Heart Association) and the Althingi (the Icelandic Parliament). ARIC: The Atherosclerosis Risk in Communities Study is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute contracts N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021 and N01-HC-55022, and grants R01HL087641, R01HL59367, R37HL051021, R01HL086694 and U10HL054512; National Human Genome Research Institute contract U01HG004402; and National Institutes of Health contract HHSN268200625226C. Infrastructure was partly supported by Grant Number UL1RR025005, a component of the National Institutes of Health and NIH Roadmap for Medical Research. A.K. is supported by a German Research Foundation Fellowship. CHS: The Cardiovascular Health Study was supported by contract numbers N01-HC-85079 through N01-HC-85086, N01-HC-35129, N01 HC-15103, N01 HC-55222, N01-HC-75150, N01-HC-45133, grant numbers U01 HL080295 and R01 HL087652 from the National Heart, Lung, and Blood Institute. A full list of principal CHS investigators and institutions can be found at http://www. chs-nhlbi.org/pi.htm. FHS: The National Heart, Lung, and Blood Institute’s Framingham Heart Study is a joint project of the National Institutes of Health and Boston University School of Medicine and was supported by the National Heart, Lung, and Blood Institute’s Framingham Heart Study (contract No. N01-HC-25195) and its contract with Affymetrix, Inc. for genotyping services (contract No. N02-HL-6-4278). Analyses reflect the efforts and resource development from the Framingham Heart Study investigators participating in the SNP Health Association Resource (SHARe) project. A portion of this research was conducted using the Linux Cluster for Genetic Analysis (LinGA-II) funded by the Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center. RS: The Rotterdam Study is supported by the Erasmus Medical Center and Erasmus University Rotterdam; the Netherlands Organization for Scientific Research; the Netherlands Organization for Health Research and Development (ZonMw); the Research Institute for Diseases in the Elderly (RIDE); The Netherlands Heart Foundation; the Ministry of Education, Culture and Science; the Ministry of Health Welfare and Sports; the European Commission (DG XII); the Municipality of Rotterdam and the ErasmusMC translational research fund (2004-44). Support for genotyping was provided by the Netherlands Organization for Scientific Research (NWO Groot, 175.010.2005.011, 911.03.012) and Research Institute for Diseases in the Elderly (014.93.015; RIDE2). This study was supported by the Netherlands Genomics Initiative (NGI)/Netherlands Organisation for Scientific Research (NWO) project nr. 050-060-810. We thank P. Arp, M. Jhamai, M. Moorhouse, M. Verkerk and S. Bervoets for their help in creating the database and M. Struchalin for his contributions to the imputations of the data. The authors are grateful to the study participants, the staff from the Rotterdam Study and the participating general practioners and pharmacists.

PY - 2009/6

Y1 - 2009/6

N2 - Blood pressure is a major cardiovascular disease risk factor. To date, few variants associated with interindividual blood pressure variation have been identified and replicated. Here we report results of a genome-wide association study of systolic (SBP) and diastolic (DBP) blood pressure and hypertension in the CHARGE Consortium (n = 29,136), identifying 13 SNPs for SBP, 20 for DBP and 10 for hypertension at P 4 × 10 7. The top ten loci for SBP and DBP were incorporated into a risk score; mean BP and prevalence of hypertension increased in relation to the number of risk alleles carried. When ten CHARGE SNPs for each trait were included in a joint meta-analysis with the Global BPgen Consortium (n = 34,433), four CHARGE loci attained genome-wide significance (P 5 × 10 8) for SBP (ATP2B1, CYP17A1, PLEKHA7, SH2B3), six for DBP (ATP2B1, CACNB2, CSK-ULK3, SH2B3, TBX3-TBX5, ULK4) and one for hypertension (ATP2B1). Identifying genes associated with blood pressure advances our understanding of blood pressure regulation and highlights potential drug targets for the prevention or treatment of hypertension.

AB - Blood pressure is a major cardiovascular disease risk factor. To date, few variants associated with interindividual blood pressure variation have been identified and replicated. Here we report results of a genome-wide association study of systolic (SBP) and diastolic (DBP) blood pressure and hypertension in the CHARGE Consortium (n = 29,136), identifying 13 SNPs for SBP, 20 for DBP and 10 for hypertension at P 4 × 10 7. The top ten loci for SBP and DBP were incorporated into a risk score; mean BP and prevalence of hypertension increased in relation to the number of risk alleles carried. When ten CHARGE SNPs for each trait were included in a joint meta-analysis with the Global BPgen Consortium (n = 34,433), four CHARGE loci attained genome-wide significance (P 5 × 10 8) for SBP (ATP2B1, CYP17A1, PLEKHA7, SH2B3), six for DBP (ATP2B1, CACNB2, CSK-ULK3, SH2B3, TBX3-TBX5, ULK4) and one for hypertension (ATP2B1). Identifying genes associated with blood pressure advances our understanding of blood pressure regulation and highlights potential drug targets for the prevention or treatment of hypertension.

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JO - Nature genetics

JF - Nature genetics

IS - 6

ER -

Genome-wide association study of blood pressure and hypertension

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